Intermediates for oxa-phenylene prostaglandins

ABSTRACT

This invention is a group of intermediates for preparing oxaphenylene compounds, and processes for making them. The oxaphenylene compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.

United States Patent 1191 Nelson Dec. 23, 1975 INTERMEDIATES FOROXA-PHENYLENE PROSTAGLANDINS [5 6] References Cited [75] Inventor:Norman A. Nelson, Galesburg, FOREIGN PATENTS OR APPLICATIONS Mlch-784,809 12/1972 Belgium 260/468 [73] Assignee: The Upjohn Company,Kalamazoo, Mi h Primary Examiner-Robert Gerstl A ,A t, F' MrriL.N'lFiled: J y 1974 ltorney gen or zrm o s 1e sen [21] App]. No.2 489,845[57] ABSTRACT I Related US. Application Data This invention is a groupof intermediates for prepar- [63] Continuation-impart of Ser. No.302,567, Oct. 30, oxa'phenylene compounds and processes for 1972,abandoned, which is a continuation-in-part of mg them The oxaphenylenecompounds are useful Ser. No. 121,572, March 5, 1971, abandoned. for avariety of pharmacological purposes, including anti-ulcer, inhibition ofplatelet aggregation, increase [52] US. Cl 260/473 A; 260/468 D; 260/514D; of nasal patency, labor inducement at term, and

260/520 wound healing. [51] Int. Cl. C07C 65/72; C07C 67/76 [58] FieldofSearch 260/473 A, 520 7 D'awmgs INTERMEDIATES FOR OXA-PHENYLENEPROSTAGLANDINS CROSS REFERENCE TO RELATED APPLICATIONS This applicationis a continuation-in-part of my copending application Ser. No. 302,567,filed Oct. 30, 1972, which was a continuation-in-part of my thencopending application Ser. No. 121,572, filed Mar. 5,

1971 both now abandoned.

BACKGROUND OF THE INVENTION This invention relates to compositions ofmatter, and to methods and intermediates for producing them. Inparticular, the several aspects of this invention relate to noveloxa-phenylene analogs of some of the known prostaglandins, for exampleprostaglandin E (PGE prostaglandin E (PGE progstaglandin F (PGF and PGFp prostaglandin F (PGF and PGF p prostaglandin A (PGA prostaglandin A(PGA prostaglandin B (PGB prostaglandin B (PGB the corresponding PG s,and the dihydro PG derivatives, to novel methods for producing thosenovel prostaglandin analogs, and to novel chemical intermediates usefulin those novel methods.

Each of the above-mentioned known prostaglandins is a derivative ofprostanoic acid which has the following structure and atom numbering:

'WAQ/ICOOH A systematic name for prostanoic acid is 7-[(2,B-octyl)-cyclopentl a-yl]heptanoic acid.

PGE has the following structure:

PGA has the following structure:

PGB, has the following structure:

OOH

Each of the known prostaglandins PGE PGF PGF PGA and PGB has a structurethe same as that shown for the corresponding PG compound except that ineach, C-5 and C-6 are linked with a cis carbon-carbon double bond. Forexample, PGE has the following structure:

Each of the known P6 prostaglandins has a structure the same as that ofthe PG compounds except that in each, G17 and C-l8 are linked with a ciscarboncarbon double bond. For example, PGE has the following structure:

00H VI ll Each dihydro derivative of PGE PGF PGF PGA,, and PGB has astructure the same as that shown for the corresponding PG compoundexcept that in each, C-l3 and C-l4 are linked with a carbon-carbonsingle bond. For example, dihydro-POE has the following structure:

lX YVV H0 H OH The prostaglandin formulas mentioned above each haveseveral centers of asymmetry. As drawn, formulas II to IX eachrepresents the particular optically active form of the prostaglandinobtained from certain mammalian tissues, for example, sheet vesicularglands, swine lung, and human seminal plasma, or by reduction 3 ordehydration of a prostaglandin so obtained. See, for example, Bergstromet al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. Themirror image of each formula represents a molecule of the enantiomer ofthat prostaglandin. The racemic form of the prostaglandin consists ofequal numbers of two types of molecules, one represented by one of theabove formulas and the other represented by the mirror image of thatformula. Thus, both formulas are needed to define a racemicprostaglandin. See Nature 212, 38 (1966) for discussion of thestereochemistry of the prostaglandins.

ln formulas l-IX, as well as in the formulas given hereinafter, brokenline attachments to the cyclopentane ring indicate substituents in alphaconfiguration, i.e., below the plane of the cyclopentane ring. Heavysolid line attachments to the cyclopentane ring indicate substituents inbeta configuration, i.e., above the plane of the cyclopentane ring.

Prostaglandins with carboxyl-terminated side chains attached to thecyclopentane ring in beta configuration are also known. These arederivatives of 8-iso-prostanoic acid which has the following formula:

COOH

A systematic name for 8-iso-prostanoic acid is 7-[(2B-octyl)-cyclopent-lB-yl]heptanoic acid.

The side-chain hydroxy at C- in formulas II to IX is in alpha (S)configuration. See Nature 212, 38 (1966) for discussion of thestereochemistry of the prostaglandins.

PGE PGE dihydro-PGE and the corresponding PGFa PGFp PGA, and PGEcompounds, and their esters, acylates, and pharmacologically acceptablesalts, are extremely potent in causing various biological responses. Forthat reason, these compounds are useful for pharmacological purposes.See, for example, Bergstrom et al., Pharmacol. Rev. 20, l (1968), andreferences cited therein. A few of those biological responses arestimulation of smooth muscle as shown, for example, by texts of stripsof guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation .ofother smooth muscle stimulants; antilipolytic activity as shown byantagonism of epinephrine-induced mobilization of free fatty acids orinhibition of the spontaneous release of glycerol from isolated rat fatpads; inhibition of gastric secretion in the case of the PGE and PGAcompounds as shown in dogs with secretion stimulated by food orhistamine infusion; activity on the central nervous system; controllingspasm and facilitating breathing in asthmatic conditions; decreasingblood platelet adhesiveness as shown by' platelet-to-glass adhesiveness,and inhibition of blood platelet aggregation and thrombus formationinduced by various physical stimuli, e.g., arterial injury, and variousbiochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen;and in the case of the PGE and PGE compounds, stimulation of epidermalproliferation and keratinization as shown when applied in culture toembryonic chick and rat skin segments.

Because of these biological responses; these known prostaglandins areuseful to study, prevent, control, or alleviate a widevariety ofdiseases and; undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys. v

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 pg. to about10 mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application The PGE, PGFa PGFB and PGAcompounds are useful in the treatment of asthma. For example, thesecompounds are useful as bronchodilators or as inhibitors of mediators,such as SRS-A, and histamine which are released from cells activated byan antigen-antibody complex; Thus, these compounds control spasm andfacilitate breathing in conditions such as bronchial asthma, bronchitis,bronchiectasis, pneumonia and emphysema. For these purposes, thesecompounds are administered in a variety of dosage forms, e.g., orally inthe form of tablets, capsules, or liquids; rectally in the form ofsuppositories; parenterally, subcutaneously, or intramuscularly, withintravenous administration being preferred in emergency situations; byinhalation in the form of aerosols or solutions for nebulizers; or byinsufflation in the form of powder. Doses in the range of about 0.01 to5 mg. per kg. of body weight are used to l to 4 times a day, the exactdose depending on the age, weight, and condition of the patient and onthe frequency and route of administration. For the above use theseprostaglandins can be combined advantageously with other anti-asthmaticagents, such as sympathomimetics (isoproterenol, phenylephrine,ephedrine, etc.); xanthine derivatives (theophylline and aminophylline);and corticosteroids (ACTH and predinisolone). Regarding use of thesecompounds see South African Pat. No. 681,055.

The PGE and PGA compounds are useful in mammals, including man andcertain usefulanimals, e.g., dogs and pigs, to reduce and controlexcessive gastric secrection, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 ug. to about 500 pg.per kg. of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.1 to about 20 mg. per kg. of bodyweight per day, the exact dose depending on the age, weight, andcondition of the patient or animal, and on the frequency and route ofadministration.

The PGE, PGFa and PGFp compounds are useful whenever it is desired toinhibit platelet aggregation, to reduce the adhesive character ofplatelets, and to remove or prevent the formation of thrombi in mammals,including man, rabbits, and rats. For example, these compounds areuseful in the treatment and prevention of myocardial infarcts, to treatand prevent post-operative thrombosis, to promote patency of vasculargrafts following surgery, and to treat conditions such asatherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE, PGFa and PGF compounds are especially useful as additives toblood, blood products, blood substitutes, and other fluids which areused in artificial extracorporeal circulation and perfusion of isolatedbody portions, e.g., limbs and organs, whether attached to the originalbody, detached and being preserved or prepared for transplant, orattached to a new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached,-to the recipient, or to two or all of those at a total steady state doseof about 0.001 to mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and tech niques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, PGE for example, is useful in place of or in combination withlessthan usual amounts of these known smooth muscle stimulators, forexample, to relieve the symptoms of paralytic ileus, or to control orprevent atonic uterine bleeding after abortion or delivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 pg. per kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiuminthe range 0.01 to 2 mg. per kg; of body weight per day, the exact dosedepending on the age, weight, and condition of the patient or animal.

ThePGE, PGFa and PGF ful in place of oxytocin to induce labor inpregnant female animals, including man, cows, sheep, and pigs, at ornear term, or in pregnant animals with intrauterine death of the fetusfrom about weeks to term. For this purpose, the compound is infusedintravenously at a dose of 0.01 to 50 ,ugnper kg. of body weight perminute until or near the termination of the second stage of labor, i.e.,expulsion of the fetus. These compounds are especially useful when thefemale is one or more weeks post-mature and natural labor has notstarted, or

female mammals, including humans and animals such as monkeys, rats,rabbits, dogs, cattle, and the like. By the term ovulating femalemammals is meant animals which are mature enough to ovulate but not soold that regular ovulation has ceased. For that purpose PGF for example,is administered systemically at a dose level in the range 0.01 mg. toabout 20 mg. per kg. of body weight of the female mammal, advantageouslyduring a span of time starting approximately at the time of ovulationand ending approximately at the time of menses or just prior to menses.lntravaginal and intrauterine arealternative routes of administration.Additionally, expulsion of an embryo or a fetus is accomplished bysimilar administration of the compound during the first third of thenormal mammalian gestation period. I

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e.g., diabetes mellitus, vascular diseases, andhyperthyroidism.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal dysfunction, especially those involving blockageof the renal vascular bed. Illustratively, thePGA compounds are usefulto alleviate and correct cases of edema resulting, for example, frommassive surface burns, and in the management of shock. For thesepurposes, the PGA compounds are preferably first administered byintravenous cutaneous injection or infusion in the range 0.05 to 2compounds are. use- 12 or 60 hours after the membranes have ruptured andmg. per kg. of body weight per day. e

The PGE and'PGB compounds promote and accelerate the growth of epidermalcells and keratin in animals, including humans, useful domestic animals,pets, zoological specimens, and laboratory animals. For that reason,these compounds are useful to promote and accelerate healing of skinwhich has been damaged, for example, by burns, wounds, and abrasions,and after surgery. These compounds are also useful to promote andaccelerate adherence and growth of skin autografts, especially small,deep (Davis) grafts which are intended to cover skinless areas bysubsequent outward growth rather than initially, and to retard rejectionof homografts.

For these purposes, these compounds are preferably administeredtopically at or near the cite where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings,-or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate, a wet dressing for topical application to second and/orthird degree burns of skin area to square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 1to 500 ug/ml. of the PGB compound or several times that concentration ofthe PGE compound. Especially for topical use, these prostaglandins areuseful in combination with antibiotics, for example, gentamycin,neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline,with other antibacterials, for example, mafenide hydrochloride,sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoidsteroids, for example, hydrocortisone, prednisolone, methylprednisolone,and fluprednisolone, each of those being used in the combination at theusual concentration suitable for its use alone.

The PGE and PGF compounds are useful in causing cervical dilation inpregnant and nonpregnant female mammals for purposes of gynecology andobstetrics. In labor induction and in clinical abortion produced bythese compounds, cervical dilation is also observed. In cases ofinfertility, cervical dilation produced by PGE and PGF compounds isuseful in assisting sperm movement to the uterus. Cervical dilation byprostaglandins is also useful in operative gynecology such as D and C(Cervical Dilation and Uterine Curettage) where mechanical dilation maycause performation of the uterus, cervical tears, or infections. It isalso useful in diagnostic procedures where dilation is necessary fortissue examination. For these purposes, the PGE and PGF compounds areadministered locally or systemically. PGE for example, is administeredorally or vaginally at doses of about 5 to 50 mg. per treatment of anadult female human, with from one to five treatments per 24 hour period.PGE is also administered intramuscularly or subcutaneously at doses ofabout one to 25 mg. per treatment. The exact dosages for these purposesdepend on the age, weight, and condition of the patient or animal.

The PGE, PGFoz PGF PGA, and PGB com pounds are useful in reducing theundesirable gastrointestinal effects resulting from systemicadministration of anti-inflammatory prostaglandin synthetase inhibitors, and are used for that purpose by concomitant administration of theprostaglandin and the anti-inflammatory prostaglandin synthetaseinhibitor. See Partride et al., US. Pat. No. 3,781,429, for a disclosurethat the ulcerogenic effect induced by certain non-steroidalanti-inflammatory agents in rats is inhibited by concomitant oraladministration of certain prostaglandins of the E and A series,including PGE PGE PGE l3,l4-dihydro-PGE and the corresponding 1 l-deoxy-PGE and PGA compounds. v

The anti-inflammatory synthetase inhibitor, for example, indomethacin,aspirin, or phenylbutazone is administered in any of the ways known inthe art to alleviate an inflammatory condition, for example, in anydosage regimen and by any of the known routes of systemicadministration. The prostaglandin is administered along with theanti-inflammatory prostaglandin synthetase inhibitor either by the sameroute of administration or by a different route. For example, if theanti-inflammatory substance is being administered orally, theprostaglandin is also administered orally or, alternatively, isadministered rectally in the form of a suppository or, in the case ofwomen, vaginally in the form of a suppository or a vaginal device forslow release, for example as described in US. Pat. No. 3,545,439.Alternatively, if the anti-inflammatory substance is being administeredrectally, the prostaglandin is also administered rectally or,alternatively, orally or,

in the case of women vaginally. It is especially conve-' nient when theadministration route is to be the same or both anti-inflammatorysubstance and prostaglandin, to combine both into a single dosage form.

The dosage regimen for the prostaglandin in accord with this treatmentwill depend upon a variety of factors, including the type, age, weight,sex and medical condition of the mammal, the nature and dosage regimenof the anti-inflammatory synthetase inhibitor being administered to themammal, the sensitivity of the particular individual mammal to theparticular synthetase inhibitor with regard to gastrointestinal effects,and the particular prostaglandin to be administered.

SUMMARY OF THE INVENTION It is a purpose of this invention to providenovel oxa-phenylene prostaglandin analogs, and processes for makingthem.

The novel prostaglandin analogs of this invention each have an oxaoxygen (O) and a divalent phenylene moiety in the carboxyl-terminatedside chain of the prostanoic acid structure (I) or the 8-iso-prostanoicacid structure (X). These divalent groups are located between thecarboxyl group and the cyclopentane ring; and are either in addition tothe six methylene portions of said chain or in place of one to five ofsaid methylene portions. Bonding to the phenylene ring is either ortho,meta, or para. The oxa group is between the phenylene moiety and thecarboxyl group.

Some of the novel prostaglandin analogs of this invention have inaddition, a benzene ring as part of the C-l 3 to C-20 chain of theprostanoic acid structure (I) or 8-iso-prostanoic acid structure (X).That benzene ring is present as a substituted or unsubstituted phenylmoiety attached as a substituent to one of the methylenes between C-l5and the terminal methyl of the prostanoic acid or 8-isoprostanoic acidstructure. Alternatively, the substituted or unsubstituted phenyl moietyis attached to the terminal or omega carbon of the C-l6 to C20 portionof the chain, replacing one of the hydrogens of the terminal methyl, theentire terminal methyl, or the terminal methyl plus one to four of themethylenes adjacent to that terminal methyl.

For example, five of the novel prostaglandin analogs of this inventionare represented by the formulas:

XIII

XIV

Based on its relationship to PGE and prostanoic acid, the compound offormula XI is named 3-oxa-4,5-interp-phenylene-PGE Similarly thecompound of the formula XII is namedl5(R)-3-oxa-3,6-inter-m-phenylene-4,5-dinor-l3,l4-dihydro-PGF thecompound of formula XIII is named 8-iso-3-oxa-I9-phenyl-4,7-inter-m-phenylene-S,6-dinor-PGA the compound of the formula XIV is named3-oxa-l 6-(4-chloro-phenyl)-3,5-inter-o-phenylene-4,17,18,19,20-pentanor- PGF and the compound offormula XV is named 5,6-dehydro-4-oxa-4,5-inter-m-phenylene-PGB Thesenames for the compounds of formulas XI to XV are typical of the namesusedhereinafter for the novel compounds of this invention. These namescan better be understood by reference to the structure and numberingsystem of prostanoic acid (Formula I, above). That formula has sevencarbon atoms in the carboxy-terminated chain and eight carbon atoms inthe hydroxy-containing chain. In these names, 3-oxa" and 4-oxa indicatean oxa oxygen (O-) in place of the 3-methylene and 4-methylene,respectively of the PG compound.

The use of nor, or dinor, trinor, tetranor, pentanor, hexanor, and thelike in the names for the novel compounds of this invention indicatesthe absence of one or more of the chain carbon atoms and the attachedhydrogen atoms. The number or numbers in front of nor, dinor, etc.,indicate which of the original prostanoic acid carbon atoms are missingin the named compound.

Each of the names of the novel compounds of this invention contains(inter-p-phenylene), (inter-m-phenylene), or (inter-o-phenylene),preceded by two numbers. That indicates that p-phenylene, m-phenylene,or o-phenylene has been inserted between (inter) the two carbon atoms sonumbered in the formula of prostanoic acid.

Thus, formula XIII differs from prostanoic acid in that an oxa oxygenreplaces carbon 3, carbons 5 and 6 of prostanoic acid are missing,m-phenylene has been inserted between carbons 4 and 7 of prostanoicacid, and a phenyl has been attached to carbon 19 of prostanoic acid.Formula XIII also, of course, is an A type prostaglandin, having acarbonyl oxygen and a 10:11 double bond.

Novel compounds of this invention with the carboxyl-terminated chainattached to the cyclopentane ring in beta configuration are 8isocompounds (formula X), and are so designated by using 8-iso in the name.An example is the name given above for the compound of formula XIII. IfS-iso does not appear in the name, attachment of the carboxy-terminatedchain in alpha configuration is to be assumed.

Novel compounds of this invention with epi configuration for the hydroxyat C-l5 are so designated by using 15(R) in the name. See, for example,the name given above for the formula-XII compound. Alternately, IS-betais used. See. R. S. Cahn, Journal of Chemical Education Vol. 41, pageI16 (1964) for a discussion of S and R configurations. If 15(R)" orIS-beta does not appear in the name, the natural configuration for theC-1 S-hydroxy, identified as the S configuration for PGE is to beassumed.

Some of the novel compounds of this invention differ structurally inother ways from the known prostanoic acid derivatives, having forexample, more or fewer carbon atoms in either chain, and having one ormore alkyl and/or fluoro substituents in the chains.

The following formulas represent the novel oxaphenylene compounds ofthis invention.

c n -o-cHz-cooki XXXV l c=c H (i-G C-C H /R5 (2:6 v Q H H FormulasXVI-XIX,, and XXXII represent oxa-pheny- CPHErWCHrCOORl l5 lenecompounds of the PGE type. Formulas XX-XXIII, 0 and X XXIII representoxa-phenylene compounds of CHQ'CEC'CJHEJ the PGF type. FormulasXXlV-XXVII, and XXXIV XXX represent oxa-phenylene compounds of the PGAtype. Formulas XXVIll-XXXI, and XXXV represent oxaphenylene compounds ofthe PGB type. H 6-6 In formulas XVI to XXXV, the wavy line indicates gattachment of the hydroxyl or the sidechain to the cyclopentane ring inalpha or beta configuration;

G is (1) alkyl of 2 to 10 carbon atoms, inclusive, substituted withzero, one, 2, or 3 fluoro or (2) a monovalent moiety of the formula C H-0-CH2"C0ORi CH2'cgH2g@ XXX! ("U CH CH -C-G T g wherein C,H represents avalence bond or alkylene of l to 10 carbon atoms, inclusive, substitutedwith zero, 0 CPHEP-O-CHQ'COORI one, or 2 fluoro, with l to 7 carbonatoms, inclusive,

CH2 C H between XXXI 1 40 H6 H/ C'cnH2n 5 and the ring, wherein T 15alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR wherein R is hydrogen or alkyl of one to 4 H Hcarbon atoms, inclusive, and wherein s is zero, one, 2, P P' or 3, withthe proviso that not more than two T's are other than alkyl; R ishydrogen, alkyl of one to 12 CH2 CJ HZJ carbon atoms, inclusive,cycloalkyl of 3 to 10 carbon H I atoms, inclusive, aralkyl of 7 to 12carbon atoms, inclusive, hen l, hen lsubstituted with one,2,or3 chloro IC C P y P Y 6 H C-C H2 R or alkyl of one to 4 carbon atoms, inclusive,or ethyl substituted in the B-position with 3 chloro, 2 or 3 Q bromo, or1, 2, or 3 iodo;

I Qis R OH or R H H H c H -0- -c00 C=C p CH2 R1 wherein R is hydrogen oralkyl of one to 4 carbon 2 2 aj atoms, inclusive; R and R are hydrogenor methyl; XXXIV and R is alkyl of one to4 carbon atoms, inclusive, /Hsubstitute'd'with zero, one, 2, or 3 fluoro. Likewise in formulas XVI toXXXV, C H repre- H sents a valence bond or alkylene of l to 4 carbonatoms, inclusive, with l or 2 chain carbon atoms berepresent to 6 carbonatoms, inclusive, with total chain lengths 0 to 3 carbon atoms,inclusive.

Regarding the meaning of C H C I-l and C H as defined above, the novelcompounds of this invention include compounds wherein a carbon atom ofthe phenylene moiety is attached directly to the C-7 methylene or theC-5 =CR in ortho, meta, or para orientation relative to theoxa-containing portion of the carboxyl chain. When C l-I representsalkylene, the chain of carbon atoms which connects the C-7 methylene toa carbon atom of phenylene will be one or 2 carbon atoms long. When Gl-I represents alkylene, the chain of carbon atoms which connects =CR toa carbon atom of phenylene will be one carbon atom long. C l-Irepresents a valence bond or alkylene of one to 6 carbon atoms,inclusive, with one or 2 carbon atoms between the ring and the -O-. Anyor all of these alkylene chains are unsubstituted or substituted withalkyl carbons in the form of one or more alkyl groups within the totalcarbon content of each chain as specified above, i.e., a maximum of 4carbons for C l-I 2 carbons for C l-l and 4 carbons for C H When C I-Ior C H is alkylene, it is the same as or different than C I-l 8 carbonatoms being the maximum total carbon content and 3 carbon atoms beingthe maximum total chain length for the combination of C l-I and C H and6 carbon atoms being the maximum total carbon content and 3 carbon atomsbeing the maximum total chain length for the combination of G l-l and CH To illustrate these definitions, when C I-I is ethylene, C H ismethylene, or one of them is a valence bond and the other is ethylene,but both are not ethylene. In this first illustration, where the totalchain length of C H and C H is 3 carbon atoms, up to 5 carbon atoms arein the alkyl substituents.

Formulas XVI through XXXV include the separate isomers wherein IQiseitheri! on or R OH i.e. where the hydroxyl is in either alpha(natural) or beta configuration. Referring to the prostanoic acid atomnumbering (formula I above), the point of attachment corresponds toC-l5, and, herein, regardless of the variation in the C-1 to C-7 carboxychain, these epimers are referred to as C-lS epimers.

Formulas XX-XXIII, and XXXIII wherein the C-9 hydroxyl (followingprostanoic acid atom numbering) is attached to the cyclopentane with awavy line include both PGF and PGF {3 -type compounds.

Included in Formulas XVII, XXI, XXV, and XXIX, are both the cis and thetrans compounds with respect to the C-5 to C-6 double bond in thecarboxyl-terminated side chain. In all of the compounds containing the Cto C double bond, that double bond is in trans configuration, and thechain containing that moiety is 16 attached to the cyclopentane ring inbeta configuration in compounds encompassed by formulas XVI to XXXV.

The novel oxa-phenylene compounds of this invention include racemiccompounds and both optically active enantiomeric forms thereof. Asdiscussed hereinabove, two structural formulas are required to defineaccurately these racemic compounds. The formulas as drawn herein areintended to represent compounds with the same configuration as thenaturally-occurring prostaglandins. However, for convenience in thecharts herein only a single structural formula is used, for example inChart D, to define not only the optically active form but also theracemic compounds which generally undergo the same reactions.

Formula XVI represents 3-oxa-4,5-inter-p-phenylene-PGE, (formula XIhereinabove) when C l-I is ethylene, C H is methylene, G is n-pentyl,

R is hydrogen, C l-I and C I-I are attached to the phenylene in paraorientation, and the carboxyl-terminated side chain is attached to thecyclopentane ring in alpha configuration.

With regard to formulas XVI to XXXV, examples of alkyl of one to 4carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomericforms thereof. Examples of alkyl OH to 8 carbon atoms, inclusive, arethose given above, and pentyl, hexyl, heptyl, octyl, and isomeric formsthereof. Examples of alkyl of l to 12 carbon atoms, inclusive, are thosegiven above, and nonyl, decyl, undecyl, dodecyl, and isomeric formsthereof. Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive,which includes alkyl-substituted cycloalkyl, are cyclopropyl,Z-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl,Z-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cy-

clooctyl, cyclononyl, and cyclodecyl. Examples of aralkyl of 7 to 12carbon atoms, inclusive, are benzyl, phenethyl, l-phenylethyl,2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-( 1 naphthylethyl), andl-(2-naphthylmethyl). Examples of phenyl substituted by one to 3 chloroor alkyl of one to 4 carbon atoms, inclusive, are p-chlorophenyl,m-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl,2,4,6-trichlorophenyl, p-tolyl, mtolyl, o-tolyl, p-ethylphenyl,p-tert-butylphenyl, 2,5- dimethylphenyl, 4-chloro-2methylphenyl, and2,4- dich1oro-3-methylphenyl.

Examples of alkyl of two to 10 carbon atoms, inclusive, substituted withone to 3 fluoro, are 2-fluoroethyl, 2-fluorobutyl, 3-fluorobutyl,4-fluorobutyl, 5-fluoropentyl, 4-fluoro-4-methylpentyl,3-fluoroisoheptyl, 8- fluorooctyl, 3,4-difluorobutyl,4,4-difluoropentyl, 5,5- difluoropentyl, 5,5,5-trifluoropentyl, andlO,l0,l0-trifluorodecyl.

Examples of alkylene within the various scopes of C H C H C H C I-I andC H as those are defined above, are methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, and heptamethylene, andthose alkylene with one or more Examples of i T i as defined above arephenyl, p-tolyl, m-tolyl, o-tolyl, p-fluorophenyl, m-fluorophenyl,o-fluorophenyl, pchlorophenyl, m-chlorophenyl, o-chlorophenyl,p-trifluoromethylphenyl, m-trifluoromethylphenyl,p-trifluoromethylphenyl, p-hydroxyphenyl, m-hydroxyphenyl,o-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl,p-tetrahydropyranyloxyphenyl, m-tetrahydropyranyloxyphenyl,o-tetrahydropyranyloxyphenyl, o-ethylphenyl, m-isopropylphenyl,p-tert-butylphenyl, p-butoxyphenyl, 3,4-dimethylphenyl,2,4-diethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl,2,4-dichlorophenyl, 3,4- difluorophenyl, 2-chloro-4-methylphenyl,2-fluoro-4- methoxyphenyl, 3,5-dimethyl-4-fluorophenyl, 2,6-dimethyI-4-hydroxyphenyl, and 2,4-di(trifluoromethyl)phenyl.

The novel formula XVI-XIX, and XXXII PGE-type oxa-phenylene compounds,the novel formula XX- XXIII, and XXXIII PGF -type and PGF -typeoxaphenylene compounds, the novel formula XXIV- XXVII, and XXXIVPGA-type oxa-phenylene compounds, and the novel formula XXVIII-XXXI, andXXXV PGB-type oxa-phenylene compounds each cause the biologicalresponses described above for the PGE, PGFa PGF PGA, and PGB compounds,respectively, and each of these novel compounds is accordingly usefulfor the above-described corresponding purposes, and is used for thosepurposes in the same manner as described above.

The known PGE, PGFa PGFp. PGA, and PGB compounds uniformly causemultiple biological responses even at low doses. For example, PGE andPGE both cause vasodepression and smooth muscle stimulation at the sametime they exert antilipolytic activity. Moreover, for many applications,these known prostaglandins have an inconveniently short duration ofbiological activity. In striking contrast, the novel prostaglandinanalogs of formulas XVI to XXXV are substantially more specific withregard to potency in causing prostaglandin-like biological responses,and have a substantially longer duration of biological activity.Therefore, each of these novel prostaglandin analogs is useful in placeof one of the corresponding above-mentioned known prostaglandins for atleast one of the pharmacological purposes indicated above for thelatter, and is surprisingly and unexpectedly more useful for thatpurpose because it has a different and narrower spectrum of biologicalactivity than the known prostaglandin, and therefore is more specific inits activity and causes smaller and fewer undesired side effects thanthe known prostaglandin. Moreover, because of its prolonged activity,fewer and smaller doses of the novel prostaglandin analog can frequentlybe used to attain the desired result.

To obtain the optimum combination of biological response specificity,potency, and duration of activity, certain compounds within the scope offormulas XVI to XXXV are preferred. For example, in compounds offormulas XVI, XIX, XX, XXIII, XXIV, XXVII, XXVIII, and XXXI, it ispreferred that the carboxylterminated side chain contain a total of 2 to4 chain carbon atoms, inclusive, excluding the phenylene and COOR andincluding the C-7 methylene. In other words, preferred compounds ofthese formulas are those wherein C H and C,,,H together represent zero,one, or 2 chain carbon atoms. Especially preferred compounds of theseformulas are those wherein C I-I and C H each represent a valence bond,and those wherein C l-I represents a valence bond and C l-I represents asingle chain carbon atom, especially methylene.

In compounds of formulas XVII, XVIII, XXI, XXII, XXV, XXVI, XXIX, XXX,XXXII, XXXIII, XXXIV, and XXXV, it is preferred that thecarboxyl-terminated side chain contain a total of 4 or 5 chain carbonatoms, excluding the phenylene and -COOR and including -CI-I CR =CR andCI-I C E C-. In other words, preferred compounds of these formulas arethose wherein C I-I and C H together represent zero or one chain carbonatoms. Included in these compounds are those wherein C -H and C H eachrepresent a valence bond, and those wherein C l-l represents a valencebond, and C H represents a single chain carbon atom, especiallymethylene.

As used herein, a chain carbon atom is part of the direct chain ofcarbon atoms linking the C-7 methylene or =CR to the phenylene, thephenylene to the oxa, and the oxa to COOR Thus, the chain CH(CI-I- )C(CHcontains 5 carbon atoms but only 2 chain atoms.

Another preference for the carboxyterminated side chain in compounds offormulas XVI to XXXV is that the phenylene be a meta-phenylene.

Another preference for the compounds of formulas XVI to XXXV is that R Rand R are hydrogen or methyl. All of those R groups can be hydrogen, allcan be methyl, or there can be any:of the possible combinations ofhydrogen and methyl.

Certain variations in the nature of G in the compounds of formulas XVIto XXXV are especially important. In the known PG, and PGprostaglandins, e.g., PGE the portion of the molecule corresponding to Gin formulas XVI to XXXI is n-pentyl. When G is unsubstituted alkyl orfluoro-substituted alkyl as defined above, there is a preference whichresults in compounds with optimum combinations of biological properties:namely that G is straight chain alkyl of 3 to 7 carbon atoms, inclusive,with or without a fluoro substituent at the l-position e.g., CHF(CH),,CH wherein a is one, 2, 3, 4, or 5. Especially preferred among theseare n-pentyl and l-fluoropentyl.

When G is substituted alkyl, it is preferred that the 1-position bemonoor di-substituted with one or two alkyl groups containing from oneto 4 carbon atoms,

inclusive. Especially preferred are formula XVI-to- XXXV compoundswherein G is substituted at the 1-position with methyl and/or ethyl,e.g. CH(CH- 3)( z)- 3. 2 2) 3 3)2( 2) 3 2 5)2-( 2 cH or c cH, c,H, cH,cH,, wherein c is 2, 3, or 4.

When G represents as defined above, it is preferred for compounds withoptimum combination of biological properties that C,H be a valence bond,i.e., t is zero, or alkylene of one to 4 carbon atoms, inclusive, i.e.,(CH wherein d is one, 2, 3, or 4, with or without a fluoro or alkylsubstituent on the carbon adjacent to the hydroxy-substituted carbon(C-lS in PGE e.g., -CH- F-(CH -CH(CH )(CH or -C(CH -(CH wherein e iszero, one, 2, or 3. Further, it is preferred that the phenyl ring whenpresent and substituted, be substituted at least at the para position.

In compounds of formulas XXXII to XXXV, it is preferred that C l-l bemethylene and that R be ethyl.

Another way of expressing the above preferences for G is that when G isalkyl or fluoro-substituted alkyl it be a group represented by wherein ais one 2, 3, 4, or 5, and wherein R and R are hydrogen, alkyl of one to4 carbon atoms, inclusive,

or fluoro, being the same or different, with the proviso that R isfluoro only when R is hydrogen or fluoro.

Furthermore, when G is it is preferred that when CH is alkylene orfluoro-substituted alkylene it be a group represented by wherein e is 0,l, 2, 0r 3, and wherein R and R are as defined above.

Still another preference is that Q be wherein R is as definedhereinabove.

Another advantage of the novel compounds of this invention, especiallythe preferred compounds defined hereinabove, compared with the knownprostaglandins, is that these novel compounds are administeredeffectively orally, sublingually, intravaginally, buccally, or rectally,in addition to usual intravenous, intramuscular, or subcutaneousinjection or infusion methods indicated above for the uses of the knownprostaglandins.

20 These qualities are advantageous because they facilitate maintaininguniform levels of these compounds in the body with fewer, shorter, orsmaller doses, and make possible self-administration by the patient.

The PGE, PGF PGF PGA, and PGB type oxa-phenylene compounds encompassedby formulas XVI to XXXV including the special classes of compoundsdescribed above, are used for the purposes described above in the freeacid form, in ester form, or

in pharmacologically acceptable salt form. When the ester form is used,the ester is any of those within the above definition of R However, itis preferred that the ester be alkyl of one to 12 carbon atoms,inclusive. Of those alkyl, methyl and ethyl are especially preferred foroptimum absorption of the compound by the body or experimental animalsystem; and straight-chain octyl, nonyl, decyl, undecyl, and dodecyl areespecially preferred for prolonged activity in the body or experimentalanimal.

Pharmacologically acceptable salts of these formula XVI-to-XXXVcompounds useful for the purposes described above are those withpharmacologically acceptable metal cations, ammonium, amine cations, orquaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, zinc, and iron, are within the scope of thisinvention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, a-phenylethylamine, B-phenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic,and araliphatic amines containing up to and including about 18 carbonatoms, as well as heterocyclic amines, e.g., piperidine, morpholine,pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g.,I-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine,Z-methylpyrrolidine, 1,4- dimethylpiperazine, Z-methylpiperidine, andthe like, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,N-butylethanolamine, Z-aminol-butanol, 2-amino-2-ethyl-l ,3-propanediol,Z-amino- Z-methyl-l-propanol, tris-(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)- diethanolamine,galactamine, N-methylglucamine, N- methylglucosamine, ephedrine,phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

The PGE, PGFa PGF PGA, and PCB type oxa-phenylene compounds encompassedby formulas XVI to XXXV including the special classes of compoundsdescribed above, are also used for the purposes described above in freehydroxy form or in the form wherein the hydroxy moieties are transformedto lower alkanoate moieties, e.g., OH to ---OCOCH Examples of loweralkanoate moieties are acetoxy, propionyloxy, butyryloxy, valeryloxy,hexanoyloxy, hep- 21 tanoyloxy, octanoyloxy, and branched chainalkanoyloxy isomers of those moieties. Especially preferred among thesealkanoates for the above described purposes are the acetoxy compounds.These free hydroxy and alkanoyloxy compounds are used as free acids, asesters, and in salt form all as described above.

As discussed above, the compounds of formulas XVI to XXXV areadministered in various ways for various purposes; e.g., intravenously,intramuscularly, subcutaneously, orally, intravaginally, rectally,buccally, sublingually, topically, and in the form of sterile implantsfor prolonged action. For intravenous injection or infusion, sterileaqueous isotonic solutions are preferred. For that purpose, it ispreferred because of increased water solubility that R in the formulaXVI-to-XXXV compound be hydrogen or a pharmacologically acceptablecation. For subcutaneous or intramuscular injection, sterile solutionsor suspensions of the acid, salt, or ester form in aqueous ornon-aqueous media are used. Tablets, capsules, and liquid preparationssuch as syrups, elixirs, and simple solutions, with the usualpharmaceutical carriers are used for oral sublingual administration. Forrectal or vaginal administration, suppositories prepared as known in theart are used. For tissue implants, a sterile tablet or silicone rubbercapsule or other object containing or impregnated with the substance isused.

The PGE, PGF PGF PGA and PGB type oxaphenylene compounds encompassed byformulas XVI to XXXV are produced by the reactions and proceduresdescribed and exemplified hereinafter.

The various PGF -type and PGF -type oxa-phenylene compounds encompassedby formulas XX-XX- III and XXXIII are prepared by carbonyl reduction ofthe corresponding PGE type compounds encompassed by formulas XVI-XIX andXXXIII. For example, carbonyl reduction of3-oxa-3,7-inter-m-phenylene-4,5,6- trinor-PGE gives a mixture of3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF and3-oxa-3,7-inter-mphenylene-4,5,6-trinor-PGF These ring carbonylreductions are carried out by methods known in the art for ring carbonylreductions of known prostanoic acid derivatives. See, for example,Bergstrom et al., Arkiv Kemi 19, 563 (1963), Acta Chem. Scand. 16, 969(1962), and British Specification No. 1,097,533. Any reducing agent isused which does not react with carbon-carbon double bonds or estergroups. Preferred reagents are lithium(tri-tertbutoxy)aluminum hydride,the metal borohydrides, especially sodium, potassium and zincborohydrides, and metal trialkoxy borohydrides, e.g., sodiumtrimethoxyborohydride. The mixtures of alpha and beta hydroxy reductionproducts are separated into the individual alpha and beta isomers bymethods known in the art for the separation of analogous pairs of knownisomeric prostanoic acid derivatives. See, for example, Bergstrom etal., cited above, Granstrom et al., J. Biol. Chem. 240, 457 (1965), andGren et al., J. Lipid Research 5, 117 (1964). Especially preferred assepa ration methods are partition chromatographic procedures, bothnormal and reversed phase, preparative thin layer chromatography, andcountercurrent distribution procedures.

The various PGA-type oxa-phenylene compounds encompassed by formulasXXIV-XXVII and XXXIV are prepared by acidic dehydration of thecorresponding PGE type compounds encompassed by formulas XVll-XlX andXXXll. For example, acidic dehydration of3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE gives3-oxa-3,7-inter-m-phenylene-4,5,6-trin0r-PGA These acidic dehydrationsare carried out by methods known in the art for acidic dehydrations ofknown prostanoic acid derivatives. See, for example, Pike et al., Proc.Nobel Symposium II, Stockholm (1966), lnterscience Publishers, New York,pp. 162-163 (1967); and British Specification 1,097,533. Alkanoic acidsof 2 to 6 carbon atoms, inclusive, especially acetic acid, are preferredacids for this acidic dehydration. Dilute aqueous solutions of mineralacids, e.g., hydrochloric acid, especially in the presence of asolubilizing diluent, e.g., tetrahydrofuran, are also useful as reagentsfor this acidic dehydration, although these reagents may cause partialhydrolysis of an ester reactant.

The various PGB-type oxa-phenylene compounds encompassed by formulasXXVIII-XXXI and XXXV are prepared by basic dehydration of thecorresponding PGE type compounds encompassed by formulas XVI- -XIX andXXXII, or by contacting the corresponding PGA type compounds encompassedby formulas XXIV-XXVII and XXXIV with base. For example, both3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE and3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA give3-oxa-3,7-inter-rn-phenylene-4,5,6-trinor-PGB on treatment with base.

These basic dehydrations and double bond migrations are carried out bymethods known in the art for similar reactions of known prostanoic acidderivatives. See, for example, Bergstrom et al., J. Biol. Chem. 238,3555 (1963). The base is any whose aqueous solution has pI-I greaterthan 10. Preferred bases are the alkali metal hydroxides. A mixture ofwater and sufficient of a watermiscible alkanol to give a homogeneousreaction mixture is suitable as a reaction medium. The POE-type orPGA-type compound is maintained in such a reaction medium until nofurther PGB-type compound is formed, as shown by the characteristicultraviolet light absorption near 278 mp. for the PGB type compound.

The various transformations of PGE-type oxa-phenylene compounds offormulas XVI-XIX to the corresponding PGF PGF PGA and PGB typeoxaphenylene compounds are shown in Chart A, wherein G, Q, R and are asdefined above, wherein E is -CI-l CI-IR or trans-CH=CR wherein R and Rare hydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein Jis wherein V is C H cis or trans wherein C H C,H C H R and R are asdefined above, and wherein C H represents alkylene of one to 6 carbonatoms, inclusive, with one, 2, or 3 carbon atoms between O- and COOR Thevarious l3,l4-dihydroPGE PGF PGA,, and -PGB type oxa-phenylene compoundsencompassed by formulas XIX, XXIII, XXVII, and XXXI are prepared bycarbon-carbon double bond reduction of the corresponding PGE, PGF, PGA,and PGB type compound containing a trans double bond in thehydroxy-containing side chain. A cis or trans double bond or a triplebond can also be present in the carboxy-terminated side chain of theunsaturated reactant, and will be reduced at the same time to CI-I CI-IFor example, 13,14-dihydro-3-oxa-3 ,7-inter-m-phenylene-4,5,6-trinor-PGE is produced by reduction of 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE or 5,6-dehydro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE These reductions arecarried out by reacting with the unsaturated PGE, PGF PGF PGA, or PGBtype oxa-phenylene compound with diimide, following the generalprocedure described by van Tamelen et al., J. Am. Chem. Soc. 83,3725

CHART A T26 H0 cn-y-cooRt E ll carbonyl reduction R26 R26 0 l lH-J'-COOR H*J'-COOR acid I E -C-G E '"CG I 0 ii base base CH-J'-COOR E'-C-G (1961). See also Fieser et al., Topics in Organic Chemistry,Reinhold Publishing Corp., New York, pp. 432-434 (1963) and referencescited therein. The unsaturated acid or ester reactant is mixed with asalt azodiformic acid, preferably an alkali metal salt such as thedisodium or dipotassium salt, in the presence of an inert diluent,preferably a lower alkanol such as methanol or ethanol, and preferablyin the absence of substantial amounts of water. At least one molecular"equivalent of the azodiformic acid salt is used for each multiple bondequivalent of the unsaturated reactant. The resulting suspension is thenstirred, preferably with exclusion of oxygen, and the mixture is madeacid, advantageously with a carboxylic acid such as acetic acid. When areactant wherein R is hydrogen is used, the carboxylic acid reactantalso serves to acidify an equivalent amount of the azodiformic acidsalt. A reaction temperature in the range of about 10 to about 40 C. isusually suitable. Within that temperature range, the reaction is usuallycomplete within less than 24 hours. The desired dihydro product is thenisolated by conventional methods, for example, evaporation of thediluent, followed by separation from inorganic materials by solventextraction.

In the case of the oxa-phenylene unsaturated PGE, PGF and PGF typereactants, the reductions to the corresponding dihydro-PGB dihydro-PGFand dihydro-PGF type oxa-phenylene compounds are also carried out bycatalytic hydrogenation. For that purpose, palladium catalysts,especially on a carbon carrier, are preferred. It is also preferred thatthe hydrogenation be carried out in the presence of an inert liquiddiluent, for example, methanol, ethanol, dioxane, ethyl acetate, and thelike. Hydrogenation pressures ranging from about atmospheric to about 50p.s.i., and hydrogenation temperatures ranging from about 10 to about C.are preferred. The resulting dihydro product is isolated from thehydrogenation reaction mixture by conventional methods, for example,removal of the catalyst by filtration or centrifugation, followed byevaporation of the solvent.

Diimide reductions and catalytic hydrogenations to produce the variousnovel formula XIX, XXIII, XXVII, and XXXI 13,14-dihydro compounds ofthis invention from the corresponding PGE, PGF, PGA and PGB typeoxa-phenylene compounds of the PG PG trans-5,6- dehydro-PG and5,6-dehydroPG series are shown in Chart B. G, J, Q, R R R and are asdefined above, and L is wherein C H C H and C l-l are as defined above.

The oxa-phenylene compounds of the PGE PGF PGA and PGB type wherein thecarbon-carbon double bond in the carboxy-terminated side chain is in cisconfiguration are prepared by reduction of the corresponding acetylenicoxa-phenylene compounds, i.e., those with a carbon-carbon triple bond inplace of said carb0n-carbon double bond. For that purpose, there areused any of the known reducing agents which reduce an acetylenic linkageto a cis-ethylenic linkage.

25 Especially preferred for that purpose are diimide, or hydrogen and acatalyst, for example, palladium on barium sulfate, especially in thepresence of pyridine. See Fieser et al., Reagents for Organic SynthelasXVI-XIX except wherein R is hydrogen, and the oxa-phenylene PGA-typecompounds of formulas XXIV-XXVII except wherein R is hydrogen arepreparedby the series of reactions shown in Chart D,

Sis, PP John Wiley and Sons, New 5 wherein G, J, R R9 and R2 are asdefined above;

York, N.Y. (1967). These G i CHART B T26 T2 CH-J'-COOR di imideCH-U-COOR1 or s hydrogen I l CHZCHRQCG H C-G catalyst (ii H Q R26 R26 H0CH-J-COOR; dl lmide CH-U-COOR a or R hydrogen c=c CH CHRs-C-G H0 H C-Gcatalyst HO H II Q Q R T26 0 CH-J'-C0OR CH-U-COOR1 di imide 9 C=C CH CHR-C-G H c-a ll If Q Q CH-J'-COOR CH-U-COOR I di imide e 9 C=C/ reductionsare shown in Chart C, wherein G, 0, R R the same as G except that T isreplaced by T, wherein R and are as defined above, and M is wherein Cl-l C l-T and --C,,H are as defined above. These oxa-phenylene ciscompounds of the PGE PGF PGF PGA and PGB type are also prepared asdescribed hereinafter.

The oxa-phenylene PGE-type compounds of formu- T is the same as T aboveexcept that R is not hydrogen; R is the same as the above definition ofR except that R does not include hydrogen; R and R are alkyl of one to 4carbon atoms, inclusive; R is alkyl of one to 5 carbon atoms, inclusive;and indicates attachment of CHR J'--COOR to the cyclopentane ring inalpha or beta configuration, and attachment of the moiety to thecyclopropane ring in exo or endo configuration.

The oxa-phenylene PGE -type compounds of formula XVI, theoxa-phenylene-S,6-dehydro-PGE type compounds of formula XVIII, theoxa-phenylene PGA -type compounds of formula XXIV and the oxaphenylene5,6-dehydro-PGA type compounds of formula XXVI are also prepared by theseries of reactions 28 R are as defined above; Z is L or C E CM'-wherein L and M' are as defined above; and indicates attachment of --CHR-Z-COOR to the cyclopentane ring in alpha or beta configuration, and

shown in Chart E, wherein G, G, R2 ,R9, R10, R13, and 5 attachment ofthe moiety to the cyclopropane CHART c H /H R26 T26/C=C I 0 0CH-CCM'-CO0R1 CH r f-cotm1 c=c c=c H E G HO H fi G H H T26 R26/C=C\ H H0l CH-CECM'-CO0R1 CH M'C0OR1 R9 R9 c c c c I I I H (2-6 I H H H 26 26 C=C0 I 0 l CH-CEC-M-COORI CH M'-c00R1 -9 9 9 c=c c=c H/ fi-G H/ lcl-o H HT26 T2s/ 0 O CH-CsC-W-COOR CH M-c00R1 -9 /R9 /R9 c=c c=c H/ c-G H/ c-G HQ Q ring in exo or endo configuration.

It should be observed regarding the series of reactions shown in ChartsD and E, that the reactions starting with glycol XXXVIII in Chart D aresimilar to the reactions starting with glycol XLV in Chart E. The onlydifferences here are the definitions of the divalent moieties J (ChartD) and Z (Chart E). J includes saturated, cis and trans ethylenic, andacetylenic divalent moieties. Z is limited to the saturated andacetylenic divalent moieties encompassed by J. In other words, finaloxa-phenylene PGE-type compounds of formula XL (Chart D) encompasscompounds of formulas XVI to XVIII. Final oxa-phenylene PGA-typecompounds of formula XLI (Chart D) encompass compounds of formulas XXIVto XXVI. On the other hand, final oxaphenylene PGE-type compounds offormula XLVII (Chart E) encompass only compounds of formulas XVI andXVIII, and final oxa-phenylene PGA-type compounds of formula XLVIII(Chart E) encompass only compounds of formula XXIV and XXVI.

As will subsequently appear, an acetylenic intermediate of formulasXXXVII, XXXVIII, or XLV is transformed by step-wise reduction to-thecorresponding cis or trans ethylenic intermediates of formulas XXXVII orXXXVIII; and an acetylenic intermediate of formulas XXXVII, XXXVIII orXLV or a cis or trans ethylenic intermediate of formulas XXXVII orXXXVIII is transformed by reduction to the corresponding saturatedintermediate of formulas XXVII, XXXVIII, or XLV.

The initial bicyclo-ketone reactant of formula XLIII in Chart E is alsoused as an initial reactant to produce the initial bicyclo-ketone cyclicketal reactant of formula XXXVI in Chart D. The following reactions willproduce cyclic ketal XXXVI, wherein Tl-IP is tetrahydropyranyl, and (bisphenyl:

The bicycle-ketone reactant of formula XLIII exists in four isomericforms, exo and endo with respect to the attachment of the CR =CRG,moiety, and cis and trans with respect to the double bond in that samemoiety. Each of those isomers separately or various mixtures thereof areused as reactants according to this invention to produce substantiallythe same final oxaphenylene PGE or PGA type product mixture.

The process for preparing either the exo or endo configuration of theformula-XLIII bicycle-ketone is known tothe art. See U.S. Pat. No.3,776,940 and Belgian Pat. No. 702,477, Derwent Farmdoc No. 30,905.

See West Germany Offenlegungsschrift No. 1,937,912; reprinted in FarmdocComplete Specifications, Book No. 14, No. 6869 R, Week R Mar. 18, 1970.

In said U.S. Pat. No. 3,776,940 a reaction sequence capable of formingexo ketone ,XLIII is as follows: The hydroxy of 3-cyclopentenol isprotected, for example, with a tetrahydropyranyl group. Then adiazoacetic acid ester is added to the double bond to give an exoendomixture of a bicyclo[3.l.0]hexane substituted at 3 with the protectedhydroxy and at 6 with an esterified carboxyl. The exo-endo mixture istreated with a base to isomerize the endo isomer in the mixture to moreof the exo isomer. Next, the carboxylate ester group at 6 is transformedto an aldehyde group, or ketone group,

wherein R is as defined above. Then, said aldehyde group or said ketogroup is transformed by the Wittig reaction, in this case to a moiety ofthe formula CR =CR G which is in exo configuration relative to thebicyclo ring structure. Next, the protective group is removed toregenerate the 3-hydroxy which is then oxidized, for example, by theJones reagent, i.e., chromic acid (see J. Chem. Soc. 39 (1946)), to givesaid via several steps cRg-(llR G XXXVI mula:

Colo- Ll l COOCHs Compound LII is prepared by reactingendo-bicyclo[3.l.0]-hex-2-ene-6-carboxylic acid methyl ester withdiborane in a mixture of tetrahydrofuran and diethyl ether, a reactiongenerally known in the art, to give endo-bicyclo[3 .l.O]-hexane-3-ol-6-carboxylic acid methyl ester which is then reactedwith dihydropyran in the presence of a catalytic amount of POCl to givethe desired compound. This is then used as described in saidOffenlegungsschrift No. 1,937,912 to produce the endo form ofbicyclo-ketone XLIII.

As for exo XLIII, the above process produces a mixture of endo-cis andendo-trans compounds. These are separated as described for theseparation of exo-cis and exo-trans XLIII, but this separation isusually not necessary, since, as mentioned above, the cis-trans mixtureis useful as a reactant in the next process step.

In the processes of said U.S. patent and said Offenlegungsschrift,certain organic halides, e.g., chlorides and bromides, are necessary toprepare the Wittig reagents used to generate the generic moiety, -CR =CRG of bicyclo-ketone XLIII. These organic chlorides and bromides 2 GCHCland G-CH-Br,

are known in the art or can be prepared by methods known in the art.

To illustrate the availability of these organic chlorides consider firstthe above-described oxa-phenylene PGE-type compounds of formulas XVI toXIX wherein R is hydrogen and G is either (1) alkyl of one to carbonatoms, inclusive, substituted with zero, one, 2, or 3 fluoro, or

wherein C,H represents a valence bond or alkylene of l to 10 carbonatoms, inclusive, substituted with zero, one, or 2fluoro, with l to 7carbon atoms, inclusive, between and the ring; wherein T is alkyl of lto 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or ORwherein R is hydrogen or alkyl of l to 4 carbon atoms, inclusive, and sis zero, one, 2, or 3, with the proviso that not more than two Ts areother than alkyl.

For those products wherein G is alkyl of two to 10 carbon atoms,substituted with 0-3 fluoro atoms, there are available the monohalohydrocarbons, e.g., bromo- (or chloro-) -ethane, -propane, -pentane,-octane, and -decane; and the monohalofluorohydrocarbons, e.g.,

CF (CH BrCI-I CH F(CI-I Cl, C H CF (CH CI, CF (CII Cl, CH (CH CF (CH CLand CH (CH CF (CH CH CI, as described in Allphatic Fluorine Compounds,A. M. Lovelace et al., Am. Chem. Soc. Monograph Series, 1958, ReinholdPubl. Corp. Those halides not available are prepared by methods known inthe art by reacting the corresponding primery alcohol GCH OI-I with PClPBr or any of the other halogenating agents useful for this purpose.

Available alcohols include CH CI-l(CF )Cl-I OH, (CH CHCI-I CH OI-I, (CH-,CCI-I OI-l, CF CI-I(CH )CI-I CH OI-I, for example. For those halidesof the formula GCH Hal wherein Hal is chloro or bromo, G is R (CI-I hbeing one, 2, 3, or 4, and R being isobutyl, tert-butyl,3,3-difluorobutyl, 4,4-difluorobutyl, or 4,4,4-trifluorobutyl, theintermediate alcohols are prepared as follows.

In the case of R being isobutyl or tert-butyl, known alcohols areconverted to bromides, thence to nitriles with sodium cyanide, thence tothe corresponding carboxylic acids by hydrolysis, and thence to thecorresponding primary alcohols by reduction, e.g. with lithium aluminumhydride, thus extending the carbon chain one carbon atom at a time untilall primary alcohols are prepared.

In the case of R being 3,3-difluorobutyl, the necessary alcohols areprepared from keto carboxylic acids of the formula, CH CO(CH ),COOI-I,wherein r is 2, 3, 4, 5, or 6. All of those acids are known. The methylesters are prepared and reacted with sulfur tetrafluoride to produce thecorresponding CH CF- (CI-I ),COOCl-I compounds, which are then reducedwith lithium aluminum hydride to CH CF- (CH ),-CH OH. These alcohols arethen transformed to the bromide or chloride by reaction with PB or PClIn the case of R being 4,4-difluorobutyl, the initial reactants are theknown dicarboxylic acids, I-IOO- C(CH ),--COOH, wherein f is 3,4, 5,6,or 7. These dicarboxylic acids are esterified to Cl-I -,OOC-(CH );COOCHand then half-saponified, for example with barium hydroxide, to giveHOOC(CH ),COOCH The free carboxyl group is transformed first to the acidchloride with thionyl chloride and then to an aldehyde by the Rosenmundreduction. Reaction of the aldehyde with sulfur tetrafluoride then givesCHF -(CH );COOCI-l which by successive treatment with lithium aluminumhydride and PBr or PCl gives the necessary bromides or chlorides, CI-IF(CH ),CI-I Br or CHF -(CH ),-CH Cl.

37 3 ln the case of R being 4 4 4-trifluorobutyl alde- TABLE I-cont1nued hydes of the formula CH OOC(CH ),CHO are prepared asdescribed above. Reduction of the alde- Intermediate Hafides hyde withsodium borohydride gives the alcohol represented by the formula CH OOC(CH ),CH OH. Reaction with PBr or 5 H (T) PCl then gives CH OOC(CH ),CHHal. Sapomfication of that ester gives the carboxylic acid which by N sT I Hal reaction with sulfur tetrafluoride gives the necessary 9 2 1 CF(CH ),-CH Br or CF --(CH );CH CL 10 g For the above reactions of SP seeUS. Pat. No. 0 I 3 Br 3,211,723 and J. Org. Chem. 27, 3164 (1962). 13 04 Cl For those products wherein R is hydrogen and G is {g i g l6 1 min:0 c1 17 1 2- F 0 c1 I8 1 4-0CH 0 C t t 19 1 s-cu, 0 Br 20 l 4-CH3 0 Br21 l 4 CSHH 0 Br the halides necessary to prepare those compounds, if 221 8 3 not readily available, are advantageously prepared by a i 0 Bl- 3reactmg the corresponding primary alcohol, 20 i2 j'g s 27 1 3-Cl l Br (U28 1 40 1 Br r %3 1 3:11] 1 a: 31 l 3-Cl 2 Br 32 l 4-Cl 2 Br w1th PClPBr HBr, or any of the other halogenating 33 1 4-F 3* Br 34 l 2-Cl 4 Bragents known 1n the art to be useful for th1s purpose. 35 1 2 CH3 0 ClSome of the readily available halides are shown in 4-CHI, Table Iwherein s, T, and t of the formula for the inter- 36 2 0 Cl mediatehalides are as defined above, and Hal is chloro, 3O 37 2 0 c bromo, oriodo. Thus, compound No. 1 of Table I is 38 2 g-gfir 0 Cl represented bythe formula wherein s and t are zero, 1 and Hal is chloro, 39 2 i-g-L, 0Cl 40 2 2CH 0 Br 35 a I .e. CI-CH 41 2 2011,, 0 Br 6-C a 42 2 3-c11, I 0Br namely a-chlorotoluene or benzyl chloride; compound 43 2 gj zi 0 No.8 of Table I 15 represented by the formula wherein 4 Cl 0 B s is zero, tis 2, and Hal is bromo, i.e. 40 44 2 i5? r 45 2 3-OCH3 0 Cl 4 0c11 ClBrcrr2 a 46 2 5355; 0

47 Z 3-OCH3 0 Br 45 S-OCH, namely l-bromo-3-phenylpropane or3-bromopropyl- 48 2 fi gg 1 Cl benzene; and compound No. 63 of Table 1represented 49 2 Z 1 Br by the formula wherein s is 3, T is methyl inthe 2-, 4- 50 2 g -gs; l Br and 5-positions with respect to the CHsubstitution, 2 k is 2, and Hal is bromo, i.e., 5O 51 2 3-0CH 1 Br 4-OCH3 H3 52 2 a 3, 1 Br .BF"( H2)s' CH3 53 2 l l H a 54 2 3-0c1-1IZ 2 Br 5540011 7 namely l-(3-bromopropyl)-2,4,5-trimethylbenzene. 55 2 r TABLE 156 2 $853 4 Intermediate Halides 57 3 2%? 0 Cl represented by theformula 1 Ha I -CH -C H -@"(T) 58 3 20-1 0 c1 4-CH3 S T t 59 3 31%? 0 c11 0 0 1 g-ggp r i 8 I 8 1 r 60 3 2011, a 0 Br 4 0 1 c1 iggn 2 8 I i 61 3201', 0 Br 7 0 2 Cl a 8 0 2 Br ecu,

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA
 2. Methyl7-(endo-6-(1-heptenyl)-3-oxobicyclo-(3.1.0)-hex-2 Alpha-yl)-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-heptanoate, a compoundaccording to claim
 1. 3. Ethyl7-(endo-6-(1-heptenyl)-3-oxobicyclo(3.1.0)-hex-2 Alpha-yl)-3-oxa-4,7-inter-o-phenylene-5,6-dinor-heptanoate, a compoundaccording to claim
 1. 4. An optically active compound of the formula 5.Methyl 7-(endo-6-(1,2-dihydroxyheptyl)-3-oxobicyclo(3.1.0)hex-2 Alpha-yl)-3-oxa-3,7-inter-m-phenylene-4, 5,6-trinorheptanoate, a compoundaccording to claim
 4. 6. Ethyl7(endo-6-(1,2-dihydroxyheptyl)-3-oxobicyclo(3.1.0)hex-2 Alpha-yl)-3-oxa-4,7-inter-o-phenylene-5,6-dinorheptanoate, a compoundaccording to claim
 4. 7. An optically active compound of the formula